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Renal pharmacology of calcitonin gene-related peptide

University of British Columbia

The existence of calcitonin gene-related peptide (CGRP) nerve fibres and CGRP receptors in the kidney and the coupling of the receptors to adenylyl cyclase suggest a possible role for CGRP in the regulation of renal microcirculation, electrolyte transport and water homeostasis. This study investigates the dose-effect relationship of CGRP on renal haemodynamics and tubular excretion in Inactin-anaesthetized, Sprague- Dawley rats. Renal arterial infusion of CGRP (0.3-300 pmol/kg/min) did not affect mean arterial pressure (MAP) or heart rate (HR). Low doses of CGRP increased renal blood flow (RBF), arterial conductance and glomerular filtration rate (GFR) but the highest dose reduced RBF and conductance without affecting GFR. High doses of CGRP also increased urine flow, and excretion of Na⁺ and K⁺. To investigate the contributions of endothelium-derived nitric oxide in the renal actions of CGRP, the nitric oxide synthase inhibitor, N[sup G] -nitro-L-arginine methyl ester (L-NAME, 2 or 20 nmol/kg) was injected into the renal artery prior to the infusion of CGRP. The renal vasodilator but not the constrictor effect of CGRP was inhibited by both doses of L-NAME. The increase in GFR by CGRP was attenuated by the low dose and abolished by the high dose of L-NAME. L-NAME did not inhibit the diuretic, natriuretic or kaliuretic effects elicited by high doses of CGRP. The involvement of the reninangiotensin system, renal sympathetic nerves and kidney prostaglandins in CGRP induced renal effects were also investigated via renal intra-arterial injection of the angiotensin II receptor antagonist losartan (0.3 and 3 (μmol/kg), the α-adrenoceptor antagonist phenoxybenzamine (3 (μmol/kg), the ganglion blocker mecamylamine (1 (μmol/kg), and the cyclo-oxygenase inhibitor indomethacin (3 μmol/kg), respectively. The vasodilator effect of low doses of CGRP and the increase in GFR were not affected by losartan, phenoxybenzamine, mecamylamine or indomethacin. The vasoconstrictor effect induced by high doses of CGRP was blocked only by phenoxybenzamine, suggesting that it is due to noradrenaline release from sympathetic nerve terminals. CGRP's diuretic, natriuretic and kaliuretic effects were similarly inhibited by losartan, phenoxybenzamine and mecamylamine. This inhibition was primarily due to low perfusion caused by the reductions in MAP and RBF. Pretreatment with indomethacin prevented CGRP's kaliuretic effect. The effects of the specific CGRP1 receptor antagonists CGRP (8-37) (1 and 10 nmol/kg) and the putative CGRP receptor antagonist, [tyr°]CGRP(28-37)(3 and 30 nmol/kg) on the renal vascular and tubular effects of CGRP were also examined. Following renal arterial injection of CGRP (8-37) or [tyr°]CGRP(28-37), a high dose of CGRP (300 pmol/kg/min) markedly reduced MAP and increased HR. CGRP(8-37) completely but [Tyr°]CGRP(28-37) incompletely inhibited the vasodilatation and increments in GFR elicited by low doses of CGRP. Both blockers abolished the renal vasoconstriction but did not inhibit the diuresis, natriuresis or kaliuresis elicited by high but non-hypotensive doses of CGRP. The study also compared the renal effects of adrenomedullin (AM), a novel vasodilator peptide which shows homology with CGRP, with those of CGRP. When injected into the renal artery, only the highest dose of AM reduced MAP whereas the highest two doses of CGRP reduced MAP. Both AM and CGRP induced similar increases in arterial conductance at all doses except for the highest dose of AM (1 nmol/kg), which caused greater vasodilatation than did CGRP. Both peptides produced similar durations of vasodilatation. CGRP's diuretic and natriuretic effects were significantly greater than those of AM. CGRP, but not AM increased K⁺ excretion and decreased urine osmolality. Our results show that AM is a more efficacious renal vasodilator but it produces less diuresis and natriuresis than does CGRP. The possible involvement of CGRP receptors in AM renal actions was also examined. Renal arterial infusion (0.001 to 1 nmol/kg) of AM did not alter MAP or HR but dose-dependently increased RBF and arterial conductance, GFR, urine flow and excretion of Na⁺ as well as K⁺. AM's renal vascular and tubular effects were not inhibited by either the low or the high dose of CGRP(8-37) or [Tyr°]CGRP(28-37). Therefore, the renal vascular and tubular effects of AM are not mediated via the activation of CGRP1 receptors.

Thesis/Dissertation

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2009-06-04

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http://hdl.handle.net/2429/8791

Pharmacology

University of British Columbia

UBCV

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